CHIKV-FBDD · Structural investigation into functionality of Chikungunya virus nsP2 in replication complex and screening of small molecules for its inhibition
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-06-07 → 2018-06-06
- EU contribution
- €195,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
Structural investigation into functionality of Chikungunya virus nsP2 in replication complex and screening of small molecules for its inhibition
Chikungunya virus (CHIKV) is a mosquito-borne medically important pathogen that affected millions of people around the world. CHIKV infection causes high fever, intense joint pain and often leads to chronic virus-induced arthritis, to which there are no specific treatments or cures. We witness recurring epidemics in the world, and with changing climates, it is spreading to wider and wider all the time. It is a debilitating disease and there is a clear necessity to develop antiviral compounds capable of eliminating persisting virus. CHIKV is an alphavirus from Togaviridae family with single-stranded positive-sense RNA genome, which replication is carried out by a complex of four viral non-structural (ns) proteins, initially produced in a form of ns-polyprotein precursor and released by proteolytic processing. Because multifunctional nsP2 plays a central role in a replication cycle of CHIKV by exhibiting various enzymatic activities and counteracting cellular defence mechanisms, it represents the most attractive target for drug design and screening. Therefore the first aim of this project was to apply structural biology approaches to elucidate spatial organization of nsP2 domains. The second aim of the project was to explore the druggability of nsP2 domains by screening recombinant proteins against libraries of chemical fragments and characterizing binding of small molecules using sensitive biophysical techniques and crystallographic analysis.
Data: CORDIS, © European Union
Project objective
Chikungunya virus (CHIKV) is a medically important pathogen that affected millions of people around the world. CHIKV infection causes high fever, intense joint pain and often leads to chronic virus-induced arthritis, thus there is a clear necessity to develop antiviral compounds capable of eliminating persisting virus. CHIKV is an alphavirus from Togaviridae family with single-stranded positive-sense RNA genome, which replication is carried out by a complex of four viral non-structural (ns) proteins, initially produced in a form of ns-polyprotein precursor and released by proteolytic processing. Because multifunctional nsP2 plays a central role in a replication cycle of CHIKV by exhibiting various enzymatic activities and counteracting cellular defence mechanisms, it represents the most attractive target for drug design and screening. Currently, the structural information regarding CHIKV ns-proteins is limited, whereas the platforms for in vitro testing the potential inhibitors are largely non-existent. Therefore the first aims of this project will be to apply structural biology approaches to elucidate spatial organization of nsP2 and to reveal its contacts with other ns-proteins in the replication complex. The druggability of nsP2 will be then explored by screening recombinant proteins against libraries of chemical fragments and characterizing binding of small molecules using sensitive biophysical techniques and crystallographic analysis. The potential of selected compounds to interfere with enzymatic or interaction properties of nsP2 will be revealed using variety of fluorescence-based assays developed in this project. The newly discovered knowledge about structural features of CHIKV nsP2, identification of novel protein surface pockets and binding molecules, and the development of functional assays for the analysis of their inhibitory potential are expected to create the ground for future elaboration of novel specific inhibitors of CHIKV.
Original text from CORDIS.
Participants
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union